ABSTRACT: Obesity is linked to greater cancer incidence and mortality across multiple tumor types. In breast cancer, metastasis is the leading cause of cancer-related deaths, and epidemiological studies have shown that obesity is associated with increased breast cancer metastasis to lung and liver. Using both diet-induced and genetic preclinical models of obesity, it was previously shown that obese adipose tissue systemically induces lung neutrophilia, which is associated with enhanced breast cancer metastasis to this site. Here we performed RNAseq on neutrophils isolated on the lungs from lf vs hf mice.
Project description:Obesity is linked to greater cancer incidence and mortality across multiple tumor types. In breast cancer, metastasis is the leading cause of cancer-related deaths, and epidemiological studies have shown that obesity is associated with increased breast cancer metastasis to lung and liver. Using both diet-induced and genetic preclinical models of obesity, it was previously shown that obese adipose tissue systemically induces lung neutrophilia, which is associated with enhanced breast cancer metastasis to this site. Here we performed RNAseq on neutrophils isolated on the lungs from lf vs hf mice.
Project description:We developed a post-menopausal orthotopic ER+ breast cancer model that we used to investigate mechanisms of obesity mediated lung metastases. Obesity altered the immune cell composition and function in the primary tumor microenvironment. To identify tumor-derived genes associated with obesity mediated lung metastases we performed RNASeq on tumors grown in lean vs obese mice. From these results we identified a hepatocyte growth factor (HGF)-c-Met (HGF receptor)-CCL2 loop recruiting metastasis-promoting cells.
Project description:The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists to utilize tissue surgically resected from lung metastatic lesions and compare their gene expression profiles with those from non-pulmonary sites, all coming from breast cancer patients. We demonstrate that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis-associated genes. Using a cohort of 72 lymph node-negative breast cancer patients, we developed a six-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the six-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we demonstrated that the signature improves risk stratification independently of known standard clinical parameters and a previously established lung metastasis signature based on an experimental breast cancer metastasis model. Experiment Overall Design: We used microarrays to identify lung metastasis-related genes in a series of 23 patients with breast cancer metastases. No replicate, no reference sample.
Project description:Younger age and obesity increase the incidence and rates of metastasis of triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The tissue microenvironment, specifically the extracellular matrix (ECM), is known to promote tumor invasion and metastasis. We sought to characterize the effect of both age and obesity on the ECM of liver tissue. We used a diet-induced obesity (DIO) model where 10-week-old female mice were fed a high-fat diet (HFD) for 12 weeks or a control chow diet (CD) where time points were every 4 weeks to monitor age and obesity. We isolated liver tissue to characterize the ECM at each time point. Utilizing proteomics, we found that the early stages of obesity were sufficient to induce distinct differences in the ECM composition of the livers. ECM proteins previously implicated in TNBC invasion, Collagen V and Collagen IV, were enriched with weight gain. Together these data implicate ECM changes in the primary tumor microenvironment as mechanisms by which age and obesity contribute to breast cancer progression.
Project description:Younger age and obesity increase the incidence and rates of metastasis of triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The tissue microenvironment, specifically the extracellular matrix (ECM), is known to promote tumor invasion and metastasis. We sought to characterize the effect of both age and obesity on the ECM of mammary fat pads. We used a diet-induced obesity (DIO) model where 10-week-old female mice were fed a high-fat diet (HFD) for 16 weeks or a control chow diet (CD) where time points were every 4 weeks to monitor age and obesity HFD progression. We isolated the mammary fat pads to characterize the ECM at each time point. Utilizing proteomics, we found that the early stages of obesity were sufficient to induce distinct differences in the ECM composition of mammary fat pads that promote TNBC cell invasion. ECM proteins previously implicated in driving TNBC invasion Collagen IV and Collagen VI, were enriched with weight gain. Together these data implicate ECM changes in the primary tumor microenvironment as mechanisms by which age and obesity contribute to breast cancer progression.
Project description:Metastasis is the major cause of cancer-related mortality. In the lung metastasis, monocyte-derived macrophages (Mo-macs) exhibit a complex function. However, tumor cells how to derive lung metastasis through Mo-macs remains unclear. Here we show that a tumor-secreted protein osteoprotegerin (OPG) contributes to the lung metastasis of cancer depends on the Mo-macs by an in vivo screening. OPG binds with RANKL to block the signaling between RANKL-RANK on Mo-macs. RANKL-RANK signals induce Mo-macs to secrete CXCL10, recruiting NK cells to control the lung metastasis. Increased expression of OPG in the metastases is regulated by TGF-β. Consistent with our findings, enrichment of OPG amplifications was observed in metastatic cancer patients, and increased expression of OPG was also shown in the lung metastatic sites compared with the paired primary breast cancer samples. Overall, our findings reveal a mechanism of how tumor cells promote lung metastasis via inhibiting the function of Mo-macs.
Project description:Metastasis is the major cause of cancer-related mortality. In the lung metastasis, monocyte-derived macrophages (Mo-macs) exhibit a complex function. However, tumor cells how to derive lung metastasis through Mo-macs remains unclear. Here we show that a tumor-secreted protein osteoprotegerin (OPG) contributes to the lung metastasis of cancer depends on the Mo-macs by an in vivo screening. OPG binds with RANKL to block the signaling between RANKL-RANK on Mo-macs. RANKL-RANK signals induce Mo-macs to secrete CXCL10, recruiting NK cells to control the lung metastasis. Increased expression of OPG in the metastases is regulated by TGF-β. Consistent with our findings, enrichment of OPG amplifications was observed in metastatic cancer patients, and increased expression of OPG was also shown in the lung metastatic sites compared with the paired primary breast cancer samples. Overall, our findings reveal a mechanism of how tumor cells promote lung metastasis via inhibiting the function of Mo-macs.
Project description:Gene Expression Profiling of Breast Cancer Patients with Brain Metastases Brain metastases confer the worst prognosis of breast cancer as no therapy exists that prevents or eliminates the cancer from spreading to the brain. We developed a new computational modeling method to derive specific downstream signaling pathways that reveal unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available gene expression data of patients. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed the specific CSBs for each metastasis that satisfy that (1) CSB proteins are activated by the maximal number of enriched signaling pathways specific to this metastasis, and (2) CSB proteins involve in the most differential expressed coding-genes specific to the specific breast cancer metastasis. The identified signaling networks for the three types of metastases contain 31, 15, and 18 proteins, respectively, and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases of breast cancer. We performed in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Two known drugs, Sunitinib (FDA approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor) and Dasatinib (FDA approved for chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia), were shown to prohibit the metastatic colonization in brain. The TMH-52 cohort includes 11 patients who were examined with brain metastasis at the time of breast cancer diagnosis. The other 41 patients were examined with other organ metastasis at the time of breast cancer diagnosis.
Project description:Harmful effects of high fructose intake on health have been widely reported in epidemiological and laboratory studies. Although it has been reported that fructose promotes cancer development and progression, little is known about the underlying molecular mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. An orthotopic xenograft experiment revealed that ketohexokinase16 A-overexpressing breast cancer is highly metastatic in fructose-fed mice. Mechanistically, ketohexokinase-A moves from the cytoplasm to the nucleus during fructose stimulation, which is mediated by the nuclear importers LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and, in turn, YWHAH recruits SLUG to the CDH1 promoter, 20 which weakens cell adhesion and triggers cell migration. This study provides a new insight into the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.